Prostate cancer is the most common malignancy in men and is second only to lung cancer in terms of cancer mortalities [Cancer Facts and Figures: American Cancer Society; 2007.]. Early diagnosis of prostate cancer usually allows for successful surgical treatment of localized tumors and thus, good patient outcomes. However, as with many cancers, the treatment of the advanced disease state requires a systemic approach to inhibit the growth and spread of secondary metastases. Prostate cancers express the androgen receptor (AR) and rely on androgens for growth and survival [Isaacs J T, Isaacs W B., Nat Med 2004; 10:26-7.]. Consequently, androgen ablation therapies are the standard of care for late-stage disease. While 80% of patients with prostate cancer respond favorably to initial androgen ablation therapy, most patients experience a relapse of the disease within 1-2 years [Isaacs J T, Isaacs W B., Nat Med 2004; 10:26-7.]. Despite the unresponsiveness of the hormone-refractory disease to androgen-deprivation therapy, AR-regulated signaling pathways remain active and are necessary for cancer progression [Chen C. D., et al., Nature Med 2004; 10:33-9.].
Several approaches are currently used to target the AR signaling axis in prostate cancer. Existing therapies focus on decreasing the levels of circulating androgens and/or competitively blocking the AR transcriptional complex. Specifically, gonadotropin-releasing hormone (GnRH) agonists are used to suppress the testicular production of testosterone whereas antiandrogens, such as bicalutamide, function by competitively inhibiting the interaction of androgens with AR. The initial response to either form of androgen deprivation is very high. Nevertheless, the rapid onset of resistance to these interventions highlights the need for other strategies that target the hormone-independent activities of AR.
Most of the studies on the role of androgens in prostate cancer have focused on defining the mechanisms underlying the mitotic actions of this class of hormone [Balk S. P., Nucl Recept Signal 2008; 6:e001]. However, there is a growing body of evidence that AR signaling also influences tumor cell migration and invasion. For example, different clinical trials of goserelin (a GnRH analog) in prostate cancer patients demonstrate reduced incidences of distant metastases [Lawton C. A., et al. Int J Radiation Oncology Biol Phys 2001; 49:937-46; Bolla M., et al. The Lancet 2002; 360:103-8.]. Furthermore, it has recently been reported that MDV3100, a second generation AR-antagonist, decreases the number of circulating tumor cells in approximately half of the treated patients having a castration-resistant type cancer [Scher H. I., et al. The Lancet; 375:1437-46].
Compounds of Formula I are known and have been used as dye molecules. See, for example, U.S. Pat. No. 2,820,037 which describes:
wherein R1 is selected from CN, COOH, or COCl. The dye industry has generated a number of compounds that are structurally related to those of Formula I. See, e.g., U.S. Pat. Nos. 2,835,674; 2,965,644; 2,949,467; 3,953,452; 3,960,867; 4,239,868; and 4,336,383.
Japanese Patent Application No. 2003-012516 (Sumitomo Pharmaceutical Co.) identifies compounds as Ca2+/calmodulin dependent kinase kinase (CaMKK) inhibitors. The compounds are described as Formula II:
wherein R1 and R2 are independently selected from H, halo, alkyl, or haloalkyl; and R3 is H, alkyl, or substituted alkyl, or three COOR3 groups can be substituted at any location on the naphthalene ring.
U.S. Patent Application Publication No: 2010/0105716 discloses methods of treating obesity, insulin resistance, and hyperglycemia by administering a CaMKK inhibitor compound of Formula III:
wherein R1, R2, R3, R4, R5, R6, R7, R7a, R8, R9, R10, and R11 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy; or a pharmaceutically acceptable salt or prodrug thereof.
None of these documents disclose or suggest that any of the compounds of Formula I-III would be useful in methods relating to cancer, or that CaMKKβ represents a therapeutic target in the treatment of cancers.